Vinyl chloride modifies the risk for nonalcoholic fatty liver disease

NAFLD is a major health problem in the developed world that is driven by the epidemic of obesity and metabolic
syndrome. Although the prevalence of early stage NAFLD (fatty liver) is nearly 100% in at-risk individuals, the
more severe form of the disease (NASH>fibrosis>cirrhosis>HCC) is much lower, indicating that other factors
drive interindividual risk for severe NAFLD. We hypothesize that vinyl chloride (VC) is such a factor. We have
shown that VC inhalation at concentrations relevant to human environmental exposure exacerbates experimental
NAFLD in mice by causing oxidative stress and mitochondrial dysfunction. Mitochondrial quality and abundance,
regulated by autophagy, affect the cell’s bioenergetic capacity and resistance to stress. Mitochondria also
interact with other organelles such as the endoplasmic reticulum (ER) through mitochondrial-associated
membranes (MAMs). These contact sites are sensitive to (patho)physiological conditions and maladaptive
changes to MAM dynamics have been associated with mitochondrial dysfunction. Importantly, MAMs shelter key
components/functions that control mitochondrial function, ER stress and autophagy. We hypothesize that these
events create a ‘perfect storm,’ which sensitizes the hepatocyte to the biochemical stress of NAFLD exerted by
a ‘Western’-style high-fat, high-carbohydrate diet (WD) and exacerbates injury and that improved understanding
of the biology will yield novel therapies. Aim 1. To study the impact of the interaction of VC and WD on
mitochondria/ER dynamics. Electrophilic VC metabolites cause formation of protein adducts, which can induce
mitochondria and ER stress. This damage can then be amplified through altered mitochondrial-ER crosstalk via
MAMs, impairing the cell’s ability to metabolically recover from injury. We will directly investigate the impact of
VC exposure (±WD) on the damage, function and interaction (via MAMs) of these organelles in vivo and in
complementary in vitro models. Aim 2. Analyze the role of autophagy in VC induced hepatotoxicity. The
autophagic process degrades excess and/or damaged cytosolic components and is also an important
mechanism for mitochondrial quality control through mitophagy. MAMs are also critically involved in autophagic
processes. We recently demonstrated that although VC and WD increase general autophagy, mitophagy was
decreased. We will investigate the role of autophagic regulation and test the hypothesis that reduced mitophagic
flux is a protective feature during the interaction of VC and WD. Changes in mitophagy will be monitored and
quantified. To modulate autophagy in the liver key autophagy regulators will be induced or deleted. Aim 3.
Investigate the impact of protecting against mitochondria/ER/MAM dysfunction in VC-enhanced NAFLD.
Targeting critical components to the ‘perfect storm’ caused by VC exposure, may protect from the biochemical
stress and exacerbated injury during exposure. Therefore, alleviating ER stress with a chemical chaperone, or
by upregulating endogenous chaperones may be therapeutic and will be investigated. Likewise, preventing
mitochondrial depolarization with SS-31, a mitochondria-targeted peptide, will be tested for therapeutic benefit.

Grant Number: 5R01DK133454-04
NIH Institute/Center: NIH
Principal Investigator: Juliane Beier